The formation of soft gelatin capsules is today preferably carried out in a stamping process wherein the capsule wall is assembled from two gelatin halves which are stamped out of a gelatin band and then molded. Preferably, there is utilized the Scherer process operating under the rotary die method. Herein two endless gelatin bands run against two adjacent and mutually counter-rotating molding rollers. While the gelatin bands are being pressed into the molded and so create the capsule halves, the flowable filler is provided into the thus formed capsule through an exact dosing wedge. There follows the sealing together of the capsule halves, their stamping out, a wash procedure for the freeing of attached oil, a rotational dryer step as well as an adjacent shelf drying.
The rotary die method makes possible the formation and filling of capsules in a single work stream and provides a hourly yield of up to 100,000 pieces. A typical marker for the Scherer capsules is the essential weld seam in the longitudinal direction. The Scherer process has among others, the following disadvantages.
A) In order to produce soft gelatin capsules there can only be employed gelatins whose quality varies within rather narrow parameters. For example the following specifications must be met: The gelatin types must possess a gallert hardness of approximately 100 to 200 bloom as well as having viscosity values which remain thermostable over an extended time since when the gelatin bands are poured there must be provided an equal band thickness. Thus, the viscosities of the selected gelatin types cannot, over a time period of several days at 60.degree., drop by more than about 20 to 15%.
B) The molding rollers for the formation of the gelatin capsules from the two gelatin bands must be precisely made and operate very exacting. They are therefore expensive to make and sensitive to disturbance in operation.
C) In the process of preparation of soft gelatin capsules, it is necessary to provide a climatic environment of from 20 to 30% relative humidity at 22.degree. as may deduced from the absorption isotherm of water to the gelatin capsule material. Hence, the production and packing rooms must be totally air conditioned.
D) The technique of soft gelatin capsule production, in addition to the aforementioned substantial requirements of material and air conditioning, so much know-how that only those producers specializing therein can cope with it.
E) A further disadvantage lies therein that during the stamping step, the remaining portions of the gelatin bands, the so-called net wastes, can only be reutilized to a minimal extent (about 5%) and thus up to 60% of the originally charged gelatin mass must be disposed of. These net residues are, because of the requirements of the process, contaminated with separating oils and where highly active substances are utilized as the filler material, a contamination of the stamped-out net cannot be avoided. Thus, such net residues must be treated as special waste. Furthermore, these waste materials contain substantial amount of colored pigments which make the recovery of the starting material impossible.
F) Because of production process requirements, the finished capsule is coated with a contaminating separation oil which must be removed by means of a lipoid solvent material such as cheerio, methylene chloride and the like. This process step requires technical and capital intensive expenditures in order to avoid any contamination of the soft gelatin capsules and the surrounding atmosphere by the physiologically harmful solvents. Furthermore, the treatment of soft gelatin capsules containing pharmaceutically active materials with such harmful solvents, can also cause problems since the user of the soft gelatin capsules before ingesting the thus handled soft gelatin capsules could shy away from them.
A further process for the formation of soft gelatin capsules which is well known in the art is the drop and blow process, which has been called the Globex process after its developers. Herein, a lipophilic filler material is dropped out of a jet while at the same time, warm gelatin solution flows out of a tube surrounding said jet. When dropped into a cooling fluid of predetermined density (for example paraffin oil) surface tension causes these capsules to take up a spherical shape and to solidify. Oily carrier materials are suitable as the filler substance. This process delivers seamless round capsules at a hourly production rate of up to 70,000 pieces. This drop or blow process has certain disadvantages of which the following are the most important:
a) Only oily substances can be used as the filling material.
b) The different components required by the process technology such as the oily filling material, the gelatin mass, and the cooled quenching bath (paraffin oil) can be harmonized with each other, only with considerable difficulty, since one is here concerned with a 3-phase system.
c) The residual quenching bath material (paraffin oil) must be removed with a solvent. This gives rise to the same problems as occur under Section (F) of the stamping process.
It is thus clear that the procedures known to the art for the production of soft gelatin capsules are subject to technological and economic problems. The complex requirements of the process technology create considerable difficulties for the pharmaceutical manufacturing companies who wish to install and run a production system for soft gelatin capsules. Additional problems can arise due to the lack of knowledge of the properties of gelatin. Furthermore, problems arise in the cleaning of the residual separation oil or cooling oil from the capsules, to which is added, in the Scherer process, the substantial additional burden of disposal of the net wastes.
The purpose of the present invention is to avoid the problems which arise in the production of soft gelatin capsules under the state of the art, in particular the provision of a technologically and economically relatively simple process, which a pharmaceutical production company can utilize without a great expenditure on equipping and running a production facility for soft gelatin capsules.
This task is solved thereby that in a process of the prior art, there is utilized a cooling bath of exceedingly cold fluid, for example liquid nitrogen.
In particular, the present invention provides a process for the preparation of soft gelatin capsules in a dropping process wherein the filler material is surrounded with a soft gelatin mass and inserted into a cooling bath, characterized thereby that there is utilized the cooling bath for the molding of the capsules comprises an exceedingly cold fluid which has neither any biologically hazardous or harmful residued. For the practice of the present process, twin material jets, for example concentric double capillaries, such as are used in the Globex process or are known from the "Sepharex" capsule machine of the Freund Company, may be utilized. The warmed coating material (soft gelatin mass) thus flows in the outer and the filling material in the inner capillary. The separation of the capsules can, where necessary, be timed pulse-wise or intermittently controlled.